BACKGROUND: An important characteristic of transitional cell carcinoma (TCC) is the formation of tumors in multiple sites throughout the whole urinary tracts. Two theories explain the pathophysiologic mechanisms of multifocal tumors: (1) intraluminal seeding, it indicates the multiple tumors come from a single transformed malignant cell with secondary seeding or migration at different sites, and (2) the field cancerization, carcinogens affect the urothelium at multiple sites, leading to numerous mutation and independent growth of multifocal polyclonal tumors. Multifocal urothelial carcinomas could come from intraluminal seeding or from field cancerization. However, the data of clinical behaviors between the two different tumor types are lacking. METHODS: Bilateral synchronous and metachronous primary TCC of the upper urinary tracts were derived from field cancerization. Recurrent bladder cancers following upper-tract tumors mostly come from intraluminal seeding. The recurrence, progression, and prognosis of the two different tumors were analyzed. RESULTS: Bilateral upper-tract urothelial carcinomas derived from field cancerization were frequently associated with renal insufficiency, which were more invasive and had poor prognosis than bladder tumors derived from intraluminal seeding. CONCLUSION: The clinical behaviors of the multiple urothelial tumors derived from field cancerization and from intraluminal seeding should be different.

Medulloblastomas represent a heterogeneous group of cerebellar tumors that constitute the most frequent primary pediatric solid malignancy. Molecular characterization of these tumors have led to the understanding that distinctsubtypes possess characteristic properties such as gene expression profile, histological classification, and degree of dissemination that are predictive of disease progression and prognosis. Fractionation of primary medulloblastomas has led to the appreciation of brain tumor stem cells (BTSC) that may be driving the more aggressive and malignant disease. However, the developmental origins of these cells as well as the influences of early mutations in tumor suppressors on development and tumorigenesisremain unclear. My work is geared towards understanding the impact of mutations in the key tumor suppressor genes Ptc1 and p53 on medulloblastoma formation. I first identified key differences in neural stem cell marker expression that distinguish between Ptc1 and Ptc1;p53 medulloblastomas, demonstrating that the Ptc1;p53 genotype may pre-dispose to a more malignant, stem-like tumor. Through the use of a somatic mosaic model, we describe a synergistic interaction between Ptc1 haploinsufficiency and p53 deficiency leading to developmental seeding of the cerebellar field by pre-malignant cells and term this phenomenon “developmental field cancerization.” Interestingly, we observed this premalignant colonization in the cerebellarstem cell compartment as well, resulting in an aberrant population of self-renewing cells. Upon loss-of-heterozygosity at the Ptc1 locus, the Ptc;p53 animals alone develop robust cerebellar tumorsthat possess a definable stem-like population of cells that can re-initiate metastatic secondary tumors. These findings demonstrate how early mutationsin the tumor suppressor genes, such as Ptc1 and p53, may lead to stem cell field cancerization and play an important role in determining future tumor character and prognosis.

BACKGROUND:Cancers often arise within an area of cells (e.g. an epithelial patch) that is predisposed to the development of cancer, i.e. a "field of cancerization" or "field defect." Sporadic colon cancer is characterized by an elevated mutation rate and genomic instability. If a field defect were deficient in DNA repair, DNA damages would tend to escape repair and give rise to carcinogenic mutations.PURPOSE:To determine whether reduced expression of DNA repair proteins Pms2, Ercc1 and Xpf (pairing partner of Ercc1) are early steps in progression to colon cancer.RESULTS:Tissue biopsies were taken during colonoscopies of 77 patients at 4 different risk levels for colon cancer, including 19 patients who had never had colonic neoplasia (who served as controls). In addition, 158 tissue samples were taken from tissues near or within colon cancers removed by resection and 16 tissue samples were taken near tubulovillous adenomas (TVAs) removed by resection. 568 triplicate tissue sections (a total of 1,704 tissue sections) from these tissue samples were evaluated by immunohistochemistry for 4 DNA repair proteins. Substantially reduced protein expression of Pms2, Ercc1 and Xpf occurred in field defects of up to 10 cm longitudinally distant from colon cancers or TVAs and within colon cancers. Expression of another DNA repair protein, Ku86, was infrequently reduced in these areas. When Pms2, Ercc1 or Xpf were reduced in protein expression, then either one or both of the other two proteins most often had reduced protein expression as well. The mean inner colon circumferences, from 32 resections, of the ascending, transverse and descending/sigmoid areas were measured as 6.6 cm, 5.8 cm and 6.3 cm, respectively. When combined with other measurements in the literature, this indicates the approximate mean number of colonic crypts in humans is 10 million.CONCLUSIONS:The substantial deficiencies in protein expression of DNA repair proteins Pms2, Ercc1 and Xpf in about 1 million crypts near cancers and TVAs suggests that the tumors arose in field defects that were deficient in DNA repair and that deficiencies in Pms2, Ercc1 and Xpf are early steps, often occurring together, in progression to colon cancer.

Orientador: Hélio Amante Miot / Resumo: Fundamentos: Campo de cancerização cutâneo representa uma área com alterações genômicas induzidas pela radiação ultravioleta, cujo sinal de atividade são as queratoses actínicas (QA). Tratamentos que visem sua estabilização podem reduzir a incidência de QA e de tumores cutâneos não melanoma. Estudos em terapia fotodinâmica com metil aminolevulinato (TFD-MAL) no tratamento do campo de cancerização cutâneo mostram redução de até 89% na contagem de QA, já com colchicina tópica, há redução de até 78%. Até o momento, não há estudos comparando colchicina com TFD-MAL. Esse trabalho objetiva avaliar eficácia e segurança de colchicina 0,5% creme versus TFD-MAL no tratamento do campo de cancerização dos antebraços.Casuística e métodos: Ensaio clínico aberto, controlado, randomizado, envolvendo 36 pacientes do ambulatório de Dermatologia da UNESP-Botucatu, com 3-10 QAs em cada antebraço, tratados (cada antebraço) com creme de colchicina 0,5% (2x/dia por 10 dias) ou uma sessão de TFD-MAL; reavaliados após 60 dias. A avaliação clínica foi realizada pela contagem de QAs, seus subtipos clínicos, sua escala de gravidade e escala de fotoenvelhecimento dos antebraços. Avaliação histopatológica foi realizada pelo escore KIN (Keratinocyte Intraepithelial Neoplasia), atrofia epitelial e imunohistoquímica de p53 e Ki67. Todos os pacientes incluídos no estudo e randomizados fizeram parte da população ITT (intention to treat). Os dados do único dropout foram imputados como LOCF (last observed car... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Orientador: Hélio Amante Miot / Resumo: O tratamento do campo de cancerização tem o intuito de evitar a progressão das lesões pré-malignas ou desenvolvimento de lesões subclínicas, como forma de prevenção da carcinogênese. Existem diversas propostas de tratamento, porém, há poucos estudos com nicotinamida oral, nenhum comparando a eficácia entre 5-fluorouracil (5FU) tópico com fotoproteção, ou na sua associação com a nicotinamida oral. Objetivos: Avaliação da eficácia da nicotinamida oral, versus 5FU tópico intermitente, e fotoproteção, no tratamento do campo de cancerização cutâneo e queratoses actínicas (QA). Casuística e métodos: Desenho: ensaio clínico randomizado (em blocos), controlado (intrasujeito), duplo cego, fatorial. Participantes: pacientes imunocompetentes, que continham entre três e dez QA cada antebraço, selecionados durante os atendimentos do ambulatório oncológico do serviço de dermatologia da Faculdade de Medicina de Botucatu – UNESP no período de março a setembro de 2016. Houve randomização em blocos e alocação em grupos dos pacientes e antebraços. Intervenção: um grupo recebeu nicotinamida 500mg, via oral, cada 12h, e o outro, placebo. Um dos antebraços recebeu 5FU 5% creme, noturno, 3x por semana, e ambos, filtro solar (FPS 30) diurno. A duração dos tratamentos foi de 120 dias. Os pacientes foram avaliados nos momentos: T0 e T120 para avaliação clínica (contagem de QA, escore de gravidade de QA e escore de fotoenvelhecimento) e biópsia de pele para avaliação do grau de neoplasia intraepitelial... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: The treatment of the skin field cancerization is aimed at preventing the progression of premalignant lesions or the development of subclinical lesions as a way of preventing carcinogenesis. There are several treatment proposals, however, there are few studies with oral nicotinamide, none comparing the efficacy of topical 5-fluorouracil (5FU) with photoprotection, or its association with oral nicotinamide. Objectives: To evaluate the efficacy of oral nicotinamide versus intermittent topical 5FU and photoprotection in the treatment of cutaneous cancer and actinic keratoses (AK). Casuistry and methods: Design: randomized (blocks), controlled (intrasubject), double blind, factorial clinical trial. Participants: immunocompetent patients, who had between 3 and 10 AK each forearm, selected during the visits of the oncology outpatient clinic of the dermatology department of Botucatu Medical School - UNESP from March to September, 2016. There was randomization in blocks and allocation in Groups of patients and forearms. Intervention: one group received nicotinamide 500mg, orally every 12h, and the other, placebo. One of the forearms received 5FU 5% cream, overnight, 3x per week, and both, daytime (SPF 30) sunscreen. The duration of the treatments was 120 days. The patients were evaluated at the moments: T0 and T120 for clinical evaluation (AK score, AK severity score and photoaging score) and skin biopsy for evaluation of the levels of keratinocyte intraepithelial neoplasi... (Complete abstract click electronic access below) / Mestre

Submitted by Eliane Roio Ferreira null (eliane_roio@yahoo.com.br) on 2018-07-22T17:04:37Z No. of bitstreams: 1 Dissertacao Eliane 31-07-2017 (Salvo Automaticamente) repositorio.pdf: 1376384 bytes, checksum: fe63f38c9413fbb73b267ecfae5dfb34 (MD5) / Approved for entry into archive by Sulamita Selma C Colnago null (sulamita@btu.unesp.br) on 2018-07-23T13:30:44Z (GMT) No. of bitstreams: 1 ferreira_er_me_bot.pdf: 1376384 bytes, checksum: fe63f38c9413fbb73b267ecfae5dfb34 (MD5) / Made available in DSpace on 2018-07-23T13:30:45Z (GMT). No. of bitstreams: 1 ferreira_er_me_bot.pdf: 1376384 bytes, checksum: fe63f38c9413fbb73b267ecfae5dfb34 (MD5) Previous issue date: 2017-08-24 / O tratamento do campo de cancerização tem o intuito de evitar a progressão das lesões pré-malignas ou desenvolvimento de lesões subclínicas, como forma de prevenção da carcinogênese. Existem diversas propostas de tratamento, porém, há poucos estudos com nicotinamida oral, nenhum comparando a eficácia entre 5-fluorouracil (5FU) tópico com fotoproteção, ou na sua associação com a nicotinamida oral. Objetivos: Avaliação da eficácia da nicotinamida oral, versus 5FU tópico intermitente, e fotoproteção, no tratamento do campo de cancerização cutâneo e queratoses actínicas (QA). Casuística e métodos: Desenho: ensaio clínico randomizado (em blocos), controlado (intrasujeito), duplo cego, fatorial. Participantes: pacientes imunocompetentes, que continham entre três e dez QA cada antebraço, selecionados durante os atendimentos do ambulatório oncológico do serviço de dermatologia da Faculdade de Medicina de Botucatu – UNESP no período de março a setembro de 2016. Houve randomização em blocos e alocação em grupos dos pacientes e antebraços. Intervenção: um grupo recebeu nicotinamida 500mg, via oral, cada 12h, e o outro, placebo. Um dos antebraços recebeu 5FU 5% creme, noturno, 3x por semana, e ambos, filtro solar (FPS 30) diurno. A duração dos tratamentos foi de 120 dias. Os pacientes foram avaliados nos momentos: T0 e T120 para avaliação clínica (contagem de QA, escore de gravidade de QA e escore de fotoenvelhecimento) e biópsia de pele para avaliação do grau de neoplasia intraepitelial dos queratinótitos (KIN), p53 e ki67. Foram avaliados ainda os efeitos adversos no T14. Desfechos: foram analisados por intenção de tratamento (ITT), e os dropouts imputados com os valores da última avaliação disponíveis (LOCF). Os grupos foram comparados por modelo linear generalizado de efeitos mistos. Resultados: Foram incluídos 36 participantes (72 antebraços). A média de idade foi 71,6 (8,6) anos, fototipos I e II prevaleceram (94%) e 61% eram do sexo feminino. Houve redução na contagem de QA para nicotinamida com 5FU (-71%) e com filtro solar (-50%), assim como para placebo e 5FU (-62%) e filtro solar (-60%), 5FU apresentou superioridade ao FPS (p<0,05). O clearance parcial de QA (>50%), apresentou redução para todos os subgrupos (-83%; -50%; -72%; -61%), com superioridade para 5FU (p<0,05). O clearance total de QA não apresentou diferença entre os tratamentos (p=0,72,). Houve redução do escore de gravidade de QA (-74%; -62%; -81%; -64%) e de fotoenvelhecimento (-10%; -6%; -22%; -8%), sem diferença entre os grupos (p>0,2). Os principais efeitos adversos observados foram eritema (50%) e dor local (5%) com uso de 5-FU, epigastralgia e náusea com nicotinamida (5%). Houve redução no escore KIN em todos os grupos (p<0,05), sem diferença entre os subgrupos. Houve redução da atrofia epitelial em todos os tratamentos (p<0,05), com superioridade para 5FU (p<0,05). Houve redução do escore Ki67 em ambos os tratamentos (p<0,05), com maior redução no grupo que recebeu nicotinamida (p<0,05). Para p53 não houve diferença entre os tratamentos (p=0,81). Ocorreram 3 dropouts. Conclusão: 5-FU tópico reduz a atividade do campo de cancerização de forma mais eficaz que o filtro solar quanto à contagem e ao clearance de QA. Nicotinamida oral não promoveu melhora clínica, mas histológica (Ki67), adicional à fotoproteção ou ao uso de 5FU. / Background: The treatment of the skin field cancerization is aimed at preventing the progression of premalignant lesions or the development of subclinical lesions as a way of preventing carcinogenesis. There are several treatment proposals, however, there are few studies with oral nicotinamide, none comparing the efficacy of topical 5-fluorouracil (5FU) with photoprotection, or its association with oral nicotinamide. Objectives: To evaluate the efficacy of oral nicotinamide versus intermittent topical 5FU and photoprotection in the treatment of cutaneous cancer and actinic keratoses (AK). Casuistry and methods: Design: randomized (blocks), controlled (intrasubject), double blind, factorial clinical trial. Participants: immunocompetent patients, who had between 3 and 10 AK each forearm, selected during the visits of the oncology outpatient clinic of the dermatology department of Botucatu Medical School - UNESP from March to September, 2016. There was randomization in blocks and allocation in Groups of patients and forearms. Intervention: one group received nicotinamide 500mg, orally every 12h, and the other, placebo. One of the forearms received 5FU 5% cream, overnight, 3x per week, and both, daytime (SPF 30) sunscreen. The duration of the treatments was 120 days. The patients were evaluated at the moments: T0 and T120 for clinical evaluation (AK score, AK severity score and photoaging score) and skin biopsy for evaluation of the levels of keratinocyte intraepithelial neoplasia (KIN), p53 and ki67. Adverse effects were also evaluated in the T14. Outcomes: were analyzed by intention to treat (ITT), and the imputed dropouts with the values of the last observation carried forward (LOCF). The groups were compared by generalized linear model of mixed effects. Results: 36 participants (72 forearms) were included. The mean age was 71.6 (8.6) years, phototypes I and II prevailed (94%) and 61% were female. There was a reduction in the counts of AK for nicotinamide with 5FU (-71%) and with sunscreen (-50%), as well as for placebo and 5FU (-62%) and sunscreen (-60%), 5FU presented SPF superiority (P <0.05). The partial clearance of AK (> 50%) presented a reduction for all subgroups (-83%, -50%, -72%, -61%), with a superiority of 5FU (p <0.05). Total clearance of AK did not show any difference between the treatments (p = 0.72,). There was a reduction in the severity score of AK (-74%, -62%, -81%, -64%) and of photoaging (-10%, -6%, -22%, -8%), with no difference between Groups (p> 0.2). The main adverse effects observed were erythema (50%) and local pain (5%) with use of 5-FU, epigastralgia and nausea with nicotinamide (5%). There was a reduction in the KIN score in all groups (p <0.05), with no difference between the subgroups. There was reduction of epithelial atrophy in all treatments (p <0.05), with superiority to 5FU (p <0.05). There was a reduction in the Ki67 score in both treatments (p <0.05), with a larger reduction in the nicotinamide group (p <0.05). For p53 there was no difference between treatments (p = 0.81). There were 3 dropouts: one per death, one refusal because the lesions improved, and one drop due to adverse local effects. Conclusion: Topical 5-FU reduces the activity of the cancerization field more effectively than the sunscreen in the counting and clearance of AK. Oral nicotinamide did not promote clinical improvement, but histological improvement (Ki67), additional to photoprotection or the use of 5FU.

Submitted by ANNA CAROLINA MIOLA (anna_fmrp@yahoo.com.br) on 2017-10-25T13:27:30Z No. of bitstreams: 1 defesa-FINAL-repositorio.pdf: 1407690 bytes, checksum: 620d293167960fc67b1031c581f71462 (MD5) / Approved for entry into archive by Monique Sasaki (sayumi_sasaki@hotmail.com) on 2017-10-31T16:10:30Z (GMT) No. of bitstreams: 1 miola_ac_me_bot.pdf: 1407690 bytes, checksum: 620d293167960fc67b1031c581f71462 (MD5) / Made available in DSpace on 2017-10-31T16:10:30Z (GMT). No. of bitstreams: 1 miola_ac_me_bot.pdf: 1407690 bytes, checksum: 620d293167960fc67b1031c581f71462 (MD5) Previous issue date: 2017-08-24 / Fundamentos: Campo de cancerização cutâneo representa uma área com alterações genômicas induzidas pela radiação ultravioleta, cujo sinal de atividade são as queratoses actínicas (QA). Tratamentos que visem sua estabilização podem reduzir a incidência de QA e de tumores cutâneos não melanoma. Estudos em terapia fotodinâmica com metil aminolevulinato (TFD-MAL) no tratamento do campo de cancerização cutâneo mostram redução de até 89% na contagem de QA, já com colchicina tópica, há redução de até 78%. Até o momento, não há estudos comparando colchicina com TFD-MAL. Esse trabalho objetiva avaliar eficácia e segurança de colchicina 0,5% creme versus TFD-MAL no tratamento do campo de cancerização dos antebraços. Casuística e métodos: Ensaio clínico aberto, controlado, randomizado, envolvendo 36 pacientes do ambulatório de Dermatologia da UNESP-Botucatu, com 3-10 QAs em cada antebraço, tratados (cada antebraço) com creme de colchicina 0,5% (2x/dia por 10 dias) ou uma sessão de TFD-MAL; reavaliados após 60 dias. A avaliação clínica foi realizada pela contagem de QAs, seus subtipos clínicos, sua escala de gravidade e escala de fotoenvelhecimento dos antebraços. Avaliação histopatológica foi realizada pelo escore KIN (Keratinocyte Intraepithelial Neoplasia), atrofia epitelial e imunohistoquímica de p53 e Ki67. Todos os pacientes incluídos no estudo e randomizados fizeram parte da população ITT (intention to treat). Os dados do único dropout foram imputados como LOCF (last observed carried forward). Resultados: Foram incluídos 36 participantes: 50% eram do sexo masculino, com idade média (dp) de 70,9 (8,6) anos e predominância de pacientes fototipos I e II (89%). O clearance total de QAs ocorreu em 6 (17%) de COL e 7 (19%) de MAL-PDT (p=0,76), e clearance parcial (> 50%) foi alcançado em 16 (44%) dos antebraços COL e 24 (67%) MAL-PDT (p=0,07). Houve redução significativa no escore da escala de fotoenvelhecimento para COL e TFD-MAL (-6% vs -6%), escore de gravidade de QA (-65% vs -73%), subtipos clínicos das QAs presentes e contagem de QA (-45% vs -40%), após as intervenções (p<0,01), sem diferenças significativas entre os grupos. Houve redução no escore KIN em ambos os grupos (p<0,01), normalizado em 28% dos pacientes MAL-PDT e 20% em COL. Houve redução da atrofia epitelial após 60 dias (p<0,01), sem diferenças entre os tratamentos (p=0,58). Houve redução significativa do escore Ki67 em ambos os tratamentos: 15% em COL e 9% em MAL-PDT, sem diferença entre os grupos (p=0,32). Houve redução do escore de p53 em 27% no grupo COL, porém, um aumento de 4% na MAL-PDT (p<0,05). Efeitos adversos foram relatados em ambos os grupos: 69% em COL e 67% em TFD-MAL. Não houve evento adverso grave. Conclusão: Colchicina 0,5% creme e TFD-MAL são eficazes e seguros no tratamento do campo de cancerização cutâneo. / Background: Skin field cancerization is an area with genomic alterations induced by ultraviolet radiation, and actinic keratosis (AK) is a sign of its activity. Treatments to stabilize it may reduce the incidence of non-melanoma skin cancers and AK. Photodynamic therapy with methyl aminolevulinate (TFD-MAL) in the treatment of skin field cancerization shows a reduction of up to 89% in the AK count, and topical colchicine, up to 78% of reduction. To date, there are no studies comparing colchicine with PDT-MAL. The aim of this study was to evaluate the efficacy and safety of colchicine 0.5% cream versus PDT-MAL in skin field cancerization treatment of the forearms. Patients and methods: A randomized, controlled clinical trial involving 36 patients from the UNESP-Botucatu Dermatology outpatient clinic, with three to 10 AKs in each forearm, treated (each forearm) with colchicine cream (2x / day for 10 days) and one session of PDT-MAL. Reassessed after 60 days. Clinical evaluation was performed by AK count, its clinical subtypes, severity scale and forearm photoaging scale. Histopathological evaluation performed by KIN (Keratinocyte Intraepithelial Neoplasia), epithelial atrophy and immunohistochemistry of p53 and Ki67. All patients included in the study and randomized were part of the ITT population (intention to treat). The only dropout was analyzed through LOCF (last observation carried forward). Results: Thirty-six participants were included: 50% were males, mean age (SD) of 70.9 (8.6) years and predominance of phototype I and II patients (89%). Total clearance of AK occurred in 6 (17%) of COL and 7 (19%) of MAL-PDT (p = 0.76), and partial clearance (> 50%) was achieved in 16 (44%) of COL and 24 (67%) of MAL-PDT (p = 0.07). There was a significant reduction in the photodamage scale for COL and PDT-MAL (-6% vs -6%), AK severity score (-65% vs -73%), clinical subtypes of the present AK and AK (-45% vs -40%) after interventions (p <0.01), with no significant differences between the groups (p> 0.24). There was a reduction in KIN score in both groups (p <0.01), normalized in 28% of MAL-PDT patients and 20% in COL. There was reduction of epithelial atrophy after 60 days (p <0.01), with no differences between treatments (p = 0.58). There was a significant reduction of the Ki67 score in both treatments: 15% in COL and 9% in MAL-PDT, with no difference between groups (p = 0.32). There was a reduction of the p53 score in 27% in the COL group, but a 4% increase in MAL-PDT (p <0.05). Adverse effects were reported in both groups: 69% in COL and 67% in PDT-MAL. There was no serious adverse event. Conclusion: Colchicine 0.5% cream and TFD-MAL are effective and safe in skin field cancerization treatment.

O conceito de campo de cancerização, em dermatologia, sugere que a pele fotodanificada tem maior potencial para o desenvolvimento de neoplasias cutâneas. A terapia fotodinâmica (TFD) é um método não invasivo para o tratamento de queratoses actínicas (QA) múltiplas, possibilitando a abordagem de todo o campo. Vinte e seis pacientes com múltiplas QAs na face foram submetidos a três sessões de TFD com metilaminolevulinato 16% (MAL) e luz vermelha, com intervalo de um mês. Biópsias foram realizadas antes e após três meses da última sessão e o material corado para hematoxilina-eosina e Weigert. O estudo imunohistoquímico foi feito para os marcadores: TP-53, pró-colageno I, Metaloproteinase-1 e Tenascina-C. A avaliação do fotoenvelhecimento global melhorou consideravelmente (p < 0,001) e a cura clínica das QAs foi de 89,5% ao final do estudo. Duas sessões mostraram ser equivalentes a três sessões de TFD. Diminuição significante do grau e extensão da atipia celular (p < 0,001), aumento das fibras colágenas (p = 0,001) e melhora do grau de elastose (p = 0,002) foram observadas. O estudo imunohistoquímico mostrou diminuição da expressão da TP-53 (p = 0,580), aumento de pró-colágeno I (p = 0,477) e de MMP-1 (p = 0,08), embora não houvesse diferença estatisticamente significante. Aumento significativo foi observado para Tenascina-C (p = 0,024). Múltiplas sessões de TFD com MAL induziram melhora clínica e histológica do campo de cancerização. A diminuição da severidade e extensão da atipia celular associada à menor expressão de TP-53 sugerem redução do potencial carcinogênico do campo / The field cancerization concept suggests that photodamaged skin has an increased risk for the development of malignant lesions. Topical photodynamic therapy (PDT) is a non-invasive therapeutic method for multiple actinic keratosis (AK), allowing the possibility of treating the entire surface. Twenty-six patients with photodamaged skin and multiple AKs on the face were submitted to three consecutive sessions of PDT with mehtylaminolevulinate 16% (MAL) and red light, one month apart. Biopsies were performed before and three months after the last treatment session, and stained for hematoxilin-eosin and Weigert. Immunohistochemestry study was performed for TP-53, pro-collagen I, Metalloproteinase-1 and Tenascin-C. The global score for photodamage improved considerably in all patients (p < 0.001). The AK clearance rate was 89.5% at the end of the study. Two treatments were similar to three MAL-PDT sessions. A significant decrease in keratinocytes atypia grade and amount was observed (p < 0.001). A significant increase in collagen deposition (p = 0.001) and improvement of solar elastosis (p = 0.002) were noticed. Immunohistochemical study showed decreased TP-53 expression although not statistically significant (p = 0.580), increased pro-collagen I and MMP-1 expressions (p = 0.477 and p = 0.08) again not statistically significant and a increased expression of Tenascin-C (p = 0.024), which was statistically significant. In conclusion, multiple sessions of MAL-PDT induced clinical and histological improvement of field cancerization. The decrease in severity and extension of keratinocytes atypia associated with a decreased expression of TP-53 suggest a reduced carcinogenic potential of the altered field

O conceito de campo de cancerização, em dermatologia, sugere que a pele fotodanificada tem maior potencial para o desenvolvimento de neoplasias cutâneas. A terapia fotodinâmica (TFD) é um método não invasivo para o tratamento de queratoses actínicas (QA) múltiplas, possibilitando a abordagem de todo o campo. Vinte e seis pacientes com múltiplas QAs na face foram submetidos a três sessões de TFD com metilaminolevulinato 16% (MAL) e luz vermelha, com intervalo de um mês. Biópsias foram realizadas antes e após três meses da última sessão e o material corado para hematoxilina-eosina e Weigert. O estudo imunohistoquímico foi feito para os marcadores: TP-53, pró-colageno I, Metaloproteinase-1 e Tenascina-C. A avaliação do fotoenvelhecimento global melhorou consideravelmente (p < 0,001) e a cura clínica das QAs foi de 89,5% ao final do estudo. Duas sessões mostraram ser equivalentes a três sessões de TFD. Diminuição significante do grau e extensão da atipia celular (p < 0,001), aumento das fibras colágenas (p = 0,001) e melhora do grau de elastose (p = 0,002) foram observadas. O estudo imunohistoquímico mostrou diminuição da expressão da TP-53 (p = 0,580), aumento de pró-colágeno I (p = 0,477) e de MMP-1 (p = 0,08), embora não houvesse diferença estatisticamente significante. Aumento significativo foi observado para Tenascina-C (p = 0,024). Múltiplas sessões de TFD com MAL induziram melhora clínica e histológica do campo de cancerização. A diminuição da severidade e extensão da atipia celular associada à menor expressão de TP-53 sugerem redução do potencial carcinogênico do campo / The field cancerization concept suggests that photodamaged skin has an increased risk for the development of malignant lesions. Topical photodynamic therapy (PDT) is a non-invasive therapeutic method for multiple actinic keratosis (AK), allowing the possibility of treating the entire surface. Twenty-six patients with photodamaged skin and multiple AKs on the face were submitted to three consecutive sessions of PDT with mehtylaminolevulinate 16% (MAL) and red light, one month apart. Biopsies were performed before and three months after the last treatment session, and stained for hematoxilin-eosin and Weigert. Immunohistochemestry study was performed for TP-53, pro-collagen I, Metalloproteinase-1 and Tenascin-C. The global score for photodamage improved considerably in all patients (p < 0.001). The AK clearance rate was 89.5% at the end of the study. Two treatments were similar to three MAL-PDT sessions. A significant decrease in keratinocytes atypia grade and amount was observed (p < 0.001). A significant increase in collagen deposition (p = 0.001) and improvement of solar elastosis (p = 0.002) were noticed. Immunohistochemical study showed decreased TP-53 expression although not statistically significant (p = 0.580), increased pro-collagen I and MMP-1 expressions (p = 0.477 and p = 0.08) again not statistically significant and a increased expression of Tenascin-C (p = 0.024), which was statistically significant. In conclusion, multiple sessions of MAL-PDT induced clinical and histological improvement of field cancerization. The decrease in severity and extension of keratinocytes atypia associated with a decreased expression of TP-53 suggest a reduced carcinogenic potential of the altered field

Squamous cell carcinoma is the most frequent malignant tumour of head and neck. Prognostic and predictive information as an individual imprint of molecular-genetic analysis of HNSCC will help to determine the best indivicual treatment. And in case of surgical appraoch the optimal resection with adequate quality of life and long-term survival. Study of early cancerogenesis in our project is based on knowledge, that histological normal mucosa next to tumor shows preneoplastic molecular alterations. Molecular genetic changes in a histological normal mucosa harbouring a tumor may play a principal role in revealing of early cancerogenesis process. Molecular-genetic analysis of cancerogenesis in HNSCC reveals prognostic and predictive factors, which are necessary for evaluation and decission for the best individual treatment. This is the concept of tailored medicine The text summarizes current knowledge of early cancerogenesis in HNSCC and presents molecular-biological trends, which are necessary to discover details of early cancerogenesis and thus to get a tool for better detection as well as treatment of malignant disease. The study is based on fragment analysis of microsatelites lesions in tumor tissue in comparison to adjacent mucosa and the healthy mucosa. Results show significant molecular-biological...